ES2298609T3 - BENZOXAZINONAS SUBSTITUTED AND USES OF THE SAME. - Google Patents

Abstract

A compound of the formula: (See formula) or a pharmaceutically acceptable salt or pro-drug thereof, wherein: Y is C or S; m is 1 when Y is C and m is 2 when Y is S; n is 1 or 2; p is 0 to 3; q is 1 to 3; Z is - (CR a R b) r - or -SO2-, where each R a and R b are hydrogen or alkyl independently; r is from 0 to 2; X is CH or N; each R 1 is independently halogen, alkyl, haloalkyl, heteroalkyl, alkoxy, cyano, -S (O) s -R c, -C (= O) -NR c R d, -SO2-NR c R d, -N ( R c) -C (= O) -R d, or -C (= O) -R c, where each R c and R d is independently hydrogen or alkyl; s is 0 to 2; R 2 is phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperidinyl, benzopiperacinilo, benzopyrrolidinyl, benzo alkylmorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl , benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triacinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, acryridinyl, acryridinyl, diatherzinyl, acryridinyl, acryridinyl, acryridinyl, acryridinyl, acryridinyl, acryridinyl, acryridinyl, acryridinyl, acryridinyl, acryridinyl, acryridinyl, optionally acceptable With one to four substituents chosen from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, -COR, - (CR¿R¿) k-COOR¿¿, or - (CR¿R¿) k-CONR¿¿R¿¿, where k is an integer from 0 to 5, where R is hydrogen, alkyl, phenyl or phenylalkyl, wherein R¿ and R¿ are independently hydrogen or alkyl, where R¿¿ and R¿ are, independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl; optionally substituted; each of R 3 and R 4 is independently hydrogen or alkyl, or R 3 and R 4 together with their shared carbons can form a 3- to 6-membered cycloalkyl ring; and each of R 5, R 6, R 7, R 8 and R 9 are independently hydrogen or alkyl, or one of R 5 and R 6 together with one of R 7, R 8 and R 9 and the atoms in between they can form a ring of 5 to 7 members.

Description

Substituted benzoxazinones and uses of same.

This invention relates to compounds substituted benzoxazinone, and associated compositions, methods for its use as therapeutic agents, and methods of preparation of same.

The actions of 5-hydroxytryptamine (5-HT) as a major modulating neurotransmitter in the brain are mediated through a number of receptor families called 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5- HT5, 5-HT6, and 5-HT7. Based on the high level of 5-HT6 receptor mRNA in the brain, it has been indicated that the 5-HT6 receptor may play a role in the pathology and treatment of disorders of the central nervous system. In particular, selective 5-HT2 and 5-HT6 ligands have been identified as potentially useful in the treatment of certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy, disorders. obsessive compulsive, mood swings, migraine, Alzheimer's disease (cognitive memory enhancement), sleep disorders, eating disorders such as anorexia, bulimia and obesity, panic attacks, acatisia, hyperactivity disorder and attention deficit ( ADHD), attention deficit syndrome (ADD), dependence on drugs of abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal damage and / or brain injuries such as hydrocephalus. These compounds are also expected to be useful in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disorder. See for example, BL Roth et al ., J. Pharmacol. Exp. Ther ., 1994 , 268 , pages 1403-14120, DR Sibley et al ., Mol. Pharmacol ., 1993 , 43 , 320-327, AJ Sleight et al ., Neurotransmission , 1995 , 11 , 1-5, and AJ Sleight et al ., Serotonin ID Research Alert , 1997 , 2 (3), 115-8.

While several modulators have been revealed of 5-hydroxytryptamine, the need for compounds that are useful in modulating 5-HT2, 5-HT6 and other receivers 5-HT.

An object of the present invention is (i) a compound of formula:

one

or a salt or pharmaceutically acceptable pro-drug of same,

where:

quad

Y is C or S;

quad

m is 1 when Y is C and m is 2 when Y is S;

quad

n is 1 or 2;

quad

p is 0 to 3;

quad

q is 1 to 3;

quad

Z is - (CR a R b) r - or -SO 2 -, where each of R a and R b is independently hydrogen or alkyl;

quad

r is from 0 to 2;

quad

X is CH or N;

quad

each R1 is independently halo, alkyl, haloalkyl, heteroalkyl, alkoxy, cyano, -S (O) s -R c, -C (= O) -NR c R d, -SO 2 -NR c R d, -N (R c) - C (= O) -R d, or

quad

-C (= O) -R c, where each of R c and R d is independently hydrogen or I rent;

quad

s is 0 to 2;

R2 is phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxidiphenyl, diphenyl, methylene diphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxilyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperidinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triacinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, acepinyl, diacepinyl or acridinyl,

optionally independently substituted with one to four substituents chosen from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, -COR, - (CR'R '') k -COOR '' ', or - (CR'R '') k -CONR '' 'R' '' ',

quad

where k is an integer from 0 to 5,

quad

where R is hydrogen, alkyl, phenyl or phenylalkyl,

quad

where R 'and R' 'are independently hydrogen or I rent,

quad

where R '' 'and R' '' 'are, independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or rental

each of R 3 and R 4 is independently hydrogen or alkyl, or R 3 and R 4 together with its shared carbon it can form a cycloalkyl ring of 3 6 members; Y

each of R 5, R 6, R 7, R 8 and R 9 is independently hydrogen or alkyl, or one of R 5 and R 6 together with one of R 7, R 8 and R 9 and the atoms in the middle they can form a ring of 5 to 7 members.

Other objects of the present invention are:

(ii) A compound of (i)

where:

quad

Y is C or S;

quad

m is 1 when Y is C and m is 2 when Y is S;

quad

n is 1;

quad

p is 0 or 1;

quad

q is 2;

quad

Z is - (CR a R b) r, where each of R a and R b is independently hydrogen or I rent;

quad

r is 1;

quad

X is N;

quad

R2 is optionally substituted aryl or optionally substituted heteroaryl;

quad

each of R3 and R4 is independently hydrogen or alkyl, or R 3 and R 4 together with their carbon shared can form a 3 to 6 membered cycloalkyl ring; Y

quad

each of R 5, R 6, R 7, R 8 and R 9 is independently hydrogen or alkyl.

(iii) The compound of (ii), where each of R a and R b is independently hydrogen or methyl; R2 it is optionally substituted phenyl, naphthyl or optionally pyridine substituted; each of R3 and R4 is independently hydrogen or methyl, or R 3 and R 4 together form a ring cyclobutyl

(iv) The compound of (iii), wherein R2 is 2-Halophenyl, 3-Halophenyl, 4-halophenyl, naphthylene-2-yl, 3-cyanophenyl, 4-cyanophenyl, 3-nitrophenyl, 3-aminophenyl, 3-methoxyphenyl, 3-ureaphenyl, 3-methylsulfonylamino-phenyl or pyridine-4-yl.

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(v) The compound of (i), wherein said compound is of the formula

2

or a salt or pharmaceutically acceptable pro-drug thereof, wherein Z, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, n, and p are as defined in (i).

(vi) The compound of (i), where said compound is of the formula

3

or a salt or pharmaceutically acceptable pro-drug thereof, wherein Z, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, n, and p are as defined in (i).

(vii) The compound of (i), wherein said compound is of formula

4

or a salt or pharmaceutically acceptable pro-drug thereof, wherein R 1, R 3, R 4, R 5, R 6, R 7, R 8, R 9 R a, R b n, r and p are as defined in (i), and where t is from 0 to 4; and every R 10 independently it is hydrogen, halo alkyl, alkoxy, cyano, nitro, amino, urea or ethanesulfonylamino.

(viii) The compound of (i), wherein said compound is of the formula

         \ vskip1.000000 \ baselineskip
      

5

         \ vskip1.000000 \ baselineskip
      

or a salt or pharmaceutically acceptable pro-drug thereof, wherein R 1, R 3, R 4, R 5, R 6, R 7, R 8, R 9 R a, R b n, r and p are as defined in (i), and where t is from 0 to 4; and every R 10 independently it is hydrogen, halo alkyl, alkoxy, cyano, nitro, amino, urea or ethanesulfonylamino.

(ix) The compound of (i) to (viii), where said compound is selected from:

4-benzyl-6-methyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4-benzyl-6-methoxy-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4- (2-Fluoro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo- [1,4] oxazin-3-one;

4- (2-Chloro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo- [1,4] oxazin-3-one;

4- (3-Chloro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo- [1,4] oxazin-3-one;

4-benzyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4-benzyl-6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4- (2-Fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one;

4- (4-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one;

4- (4-Chloro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one;

4- (4-fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4- (2-Fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4- (2-Chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4- (4-Chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

6-fluoro-4-naphthalen-2-ylmethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4- (3-Chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

3- (3-oxo-8-piperazin-1-yl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzonitrile;

4- (3-Fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one;

4-benzyl-2,2-dimethyl-8-piperazin-1-yl-4 H -benzo [1,4] -oxazin-3-one;

(R) -4-Benzyl-2-methyl-8-piperazin-1-yl-4 H -benzo [1,4] -oxazin-3-one;

4-Benzyl-6-piperazin-1-yl-4 H -benzo [1,4] oxazin-3-one;

4- (4-Fluoro-benzyl) -6-piperazin-1-yl-4 H -benzo [1,4] -oxazin-3-one;

(S) -4-Benzyl-2-methyl-8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one;

8-Piperazin-1-yl-4-pyridin-4-ylmethyl-4H-benzo [1,4] -oxazin-3-one;

4-Benzyl-6-methyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1,4] oxazin-3-one;

4-Benzyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1,4] -oxazin-3-one;

4- (1-Phenyl-ethyl) -8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4- (3-Methoxy-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one;

4- (3-Nitro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one;

4- (3-Amino-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one;

3- (3-Oxo-8-piperazin-1-yl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzonitrile;

N- [3- (3-Oxo-8-piperazin-1-yl-2,3-dihydro-benzo [1,4] -oxazin-4-ylmethyl) -phenyl] -methanesulfonamide;

4- (4-Fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4- (3-Fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

[3- (3-Oxo-8-piperazin-1-yl-2,3-dihydro-benzo [1,4] -oxazin-4-ylmethyl) -phenyl] -urea;

4- (3-Chloro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4-Benzyl-8- (3,5-dimethyl-piperazin-1-yl) -4H-benzo [1,4] -oxazin-3-one;

4- (4-Chloro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4-Benzyl-6-fluoro-2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4- (4-Chloro-benzyl) -6-fluoro-2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

6-Fluoro-4- (3-fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

6-Fluoro-4- (2-fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

6-Fluoro-4- (4-fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one

4- (3-Chloro-benzyl) -6-fluoro-2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one;

4-Benzyl-8- (3,3-dimethyl-piperazin-1-yl) -4H-benzo [1,4] -oxazin-3-one;

1-Benzyl-5-piperazin-1-yl-1H-benzo [1,3,4] oxathiazine 2,2-dioxide; Y

4-Benzyl-2,2-spiro-cyclobutan-8-piperazin-1-yl-4 H -benzo [1,4] oxazin-3-one.

(x) A pharmaceutical composition comprising an effective amount of the compound of (i) in admixture with a vehicle pharmaceutically acceptable.

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(xi) A process for the production of a substituted benzoxazinone compound, said process comprising:

contact one N-arylalkyl benzoxazinone of the formula

6

         \ vskip1.000000 \ baselineskip
      

in where:

quad

A_ {1} is a leaving group;

quad

Z, Y, R 1, R 3, R 4, m, n, and p are such as defined in (i);

quad

R2 is aryl or heteroaryl which is optionally substituted by (R 10) t, in where

quad

t is from 0 to 4;

quad

each R 10 is independently hydrogen, halo, alkyl, alkoxy, cyano, nitro, amino, urea or ethanesulfonylamino;

quad

with a heterocyclic compound of the formula:

7

         \ vskip1.000000 \ baselineskip
      

in where:

quad

q is 1 to 3; Y

quad

each of R 5, R 6, R 7, R 8 and R 9 is independently hydrogen or alkyl, or one of R 5 and R 6 together with one of R 7, R 8 and R 9 can form a ring of 5 to 7 members;

quad

in the presence of a palladium catalyst for produce the heterocyclyl-substituted compound N-arylalkyl benzoxaninone from the formula:

8

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(xii) The process of (xi), said process understands:

contact one N-arylalkyl benzoxazinone of formula

         \ vskip1.000000 \ baselineskip
      

9

         \ vskip1.000000 \ baselineskip
      

with the heterocyclic compound of formula

         \ vskip1.000000 \ baselineskip
      

10

         \ vskip1.000000 \ baselineskip
      

such that the compound heterocyclyl-substituted N-arylalkyl benzoxaninone is from the formula:

         \ vskip1.000000 \ baselineskip
      

eleven

         \ vskip1.000000 \ baselineskip
      

and R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, n, p, r and t are as described in (xi).

(xiii) The process of (xi), where the group protrusion A 1 is halo.

(xiv) Use of one or more compounds of any from (i) to (ix) for the preparation of a medicine for treatment or prevention of a diseased state of the nervous system central.

(xv) The use of (xiv), where the disease is select from psychosis, schizophrenia, manic depressions, neurological disorders, memory disorders, attention deficit, Parkinson's disease, lateral sclerosis Amyotrophic, Alzheimer's disease and Huntington's disease.

(xvi) Use of one or more compounds of any from (i) to (ix) for the preparation of a medicine for treatment or prevention of a tract disorder gastrointestinal.

The invention also provides methods for preparation, compositions comprising, and methods of using the compounds mentioned above. The methods of the invention comprise, in one embodiment,

(a) contact a N-arylalkyl benzoxazinone of the formula

         \ vskip1.000000 \ baselineskip
      

12

         \ vskip1.000000 \ baselineskip
      

in where:

quad

A_ {1} is a leaving group,

quad

n is 1 or 2;

quad

p is 0 to 3;

quad

r is from 0 to 2;

quad

t is from 0 to 4;

quad

each of R a and R b is independently hydrogen or alkyl;

quad

each R1 is independently halo, alkyl, haloalkyl, heteroalkyl, alkoxy, cyano, -S (O) s -R c, -C (= O) -NR c R d, -SO 2 -NR c R d, -N (R c) - C (= O) -R d, or -C (= O) R c, where each of R c and R d is independently hydrogen or alkyl and s is 0 to 2;

quad

each of R3 and R4 is independently hydrogen or alkyl; Y

quad

each R 10 is independently halo, alkyl, alkoxy or cyano;

quad

with a heterocyclic compound of the formula:

         \ vskip1.000000 \ baselineskip
      

13

         \ vskip1.000000 \ baselineskip
      

in where:

quad

q is 1 to 3; Y

quad

each of R 5, R 6, R 7, R 8 and R 9 is independently hydrogen or alkyl, or one of R 5 and R 6 together with one of R 7, R 8 and R 9 can form a ring of 5 to 7 members;

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quad

in the presence of a palladium catalyst for produce heterocyclyl-substituted N-arylalkyl benzoxaninone from the formula:

14

The methods may also include:

(b) contact a benzoxazinone of the formula:

fifteen

where n, p, A 1, R 1, R 3 and R 4 are as defined previously,

with an alkylating agent of the formula:

16

in where:

quad

A_ {2} is an outgoing group and can be the same or different from A1; Y

quad

r, t, R a, R b and R 10 are as is describe in (a);

to produce the N-arylalkyl Benzoxazinone of the formula

17

The invention provides substituted benzoxazinone compounds, associated compositions, methods for use as therapeutic agents, and methods of preparing them. In specific embodiments the invention provides piperazinyl-substituted benzo [1,4] oxazine-3-one compounds and associated pharmaceutical compositions, and methods for using them in the treatment of CNS diseases and gastro-intestinal tract diseases.
tinal.

Unless stated otherwise, the following terms used in this Application, including the specification and claims, have the definitions given above. It should be noted that, as used in the specification and indexed claims, forms Singular "a", "one," and "the", "the" include its plural referents unless the context indicates clearly otherwise.

"Agonist" refers to a compound that enhances the activity of another compound or receptor site.

"Alkyl" indicates the hydrocarbon fraction saturated branched or linear monovalent, consisting only of carbon and hydrogen atoms, with one to twelve atoms of carbon.

"Lower alkyl" refers to a group alkyl of one to six carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and Similar.

"Alkylene" indicates a hydrocarbon radical linear saturated divalent of one to six carbon atoms or a branched saturated divalent hydrocarbon radical from three to six carbon atoms, for example, methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and Similar.

"Alkoxy" indicates a fraction of the formula -OR, where R is an alkyl fraction as defined here. Examples of alkoxy fractions include, but are not limited to. a, methoxy, ethoxy, isopropoxy, and the like.

"Antagonist" refers to a compound that diminishes or prevents the action of another compound or site receiver.

"Aryl" indicates a hydrocarbon fraction monovalent cyclic aromatic consisting of an aromatic ring mono, bi- or tricyclic. The aryl group may optionally be substituted as defined here. Examples of aryl fractions include, but are not limited to, optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxidiphenyl, biphenyl, methylene diphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanil, benzofuranyl, benzodioxilyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof.

"Arylalkyl" and "Aralkyl", which may use interchangeably, indicate a radical -R a R b where R a is an alkylene group and R b is such an aryl group as defined here; for example benzyl, phenylethyl, 3- (3-chlorophenyl) -2-methylpentyl, and the like are examples of arylalkyl.

"Cycloalkyl" indicates a fraction monovalent saturated carbocyclic consisting of mono- or rings bicyclic Cycloalkyl may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxyl, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino, unless indicated another way. Examples of cycloalkyl fractions include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially derivatives unsaturated thereof.

"Cycloalkylalkyl" indicates a fraction of the formula -R'-R '', where R 'is alkylene and R' 'is cycloalkyl as defined herein.

"Heteroalkyl" indicates an alkyl radical as defined here where one, two or three hydrogen atoms  have been replaced with a substituent independently selected from the group consisting of -OR a, -NR b R c, and -S (O) n R d (where n is an integer of 0 a 2), understanding that the point of attachment of the radical heteroalkyl is through a carbon atom, where R a it is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R b and R c are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; and when n is 0, R d is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R d is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to. a, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethyl ethyl, 2,3-dihydroxypropyl, 1-hydroxymethyl ethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methyl-propyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonyl ethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

"Heteroaryl" indicates a monocyclic radical or bicyclic of 5 to 12 atoms in the ring with at least one ring aromatic containing one, two, or three heteroatoms in the ring selected from N, O, or S, the remaining ring atoms are C, understanding that the point of attachment of the heteroaryl radical It will be in the aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl fractions include, but are not limited to, imidazolyl optionally substituted, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl,  indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like, including partially hydrogenated derivatives thereof.

The terms "halo" and "halogen", which can be used interchangeably, they refer to a fluorine substituent,  Chlorine, bromine, or iodine.

"Haloalkyl" indicates an alkyl as it is defined here in which one or more hydrogens have been replaced with the Same or different halogens. Exemplary haloalkyls include -CH 2 Cl, -CH 2 CF 3, -CH 2 CCl 3, perfluoroalkyl (for example, -CF3), and the like.

"Heterocycloamino" indicates a ring saturated where at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

"Heterocyclyl" indicates a fraction saturated monovalent, consisting of one to three rings, incorporating one, two or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl fractions include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dihydroquinolinyl, dihydrisoquinolinyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.

"Optionally substituted", when used in association with "aryl", "phenyl", "heteroaryl" or "heterocyclyl" means an aryl, phenyl, heteroaryl or heterocyclyl which is optionally substituted independently with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxyl, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), - (CR'R '') n-COOR (where n is an integer from 0 to 5, R 'and R' 'are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or - (CR'R '') n-CONRaRb (where n is a integer from 0 to 5, R 'and R' 'are independently hydrogen or alkyl, and Ra and Rb are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).

"Outgoing group" indicates the group with the meaning conventionally associated with him in the chemistry of organic synthesis, that is, an atom or a movable group under replacement reaction conditions. Examples of groups protrusions include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, benzyloxy optionally substituted, isopropyloxy, acyloxy, and the like.

"Modulator" indicates a molecule that Interact with a target. Interactions include, but are not limited to, agonist, antagonist, and the like, as defined here.

"Optional" or "optionally" indicate that the fact or circumstance described below may happen but that does not necessarily occur, and that the description includes cases in which the event or circumstance occurs and cases in which no.

"Illness or sick state" indicates any disease, condition, symptom, or indication.

"Inert organic solvent" or "inert solvent" indicates the solvent that is inert under the reaction conditions described therein, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert- butanol, dioxane, pyridine, and the like. Unless otherwise specified, the solvents used in the reactions of the present invention are inert solvents.

"Pharmaceutically acceptable" indicates that it is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable includes those that are acceptable for veterinary use as well as those of human pharmaceutical use.

"Pharmaceutically acceptable salts" of a compound indicates salts that are pharmaceutically acceptable, such as defined here, and that possess the desired pharmacological activity of the original compound. Such salts include:

acid addition salts formed with acids inorganic such as hydrochloric acid, hydrobromic acid, acid sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, acid benzenesulfonic acid, benzoic acid, camphorsulfonic acid, acid citric, ethanesulfonic acid, fumaric acid, acid glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, acid 2-hydroxy-ethanesulfonic acid lactic acid, maleic acid, malic acid, malonic acid, acid Mandelic acid, methanesulfonic acid, muconic acid, acid 2-naphthalenesulfonic acid, propionic acid, acid salicylic acid, succinic acid, tartaric acid, acid p-toluenesulfonic acid, trimethylacetic acid, and Similar; or

salts formed when an acidic proton is present in the original compounds it is replaced by a metal ion, by example, an ion of an alkali metal, an ion alkaline earth, or an aluminum ion; or coordinated with an organic or inorganic base. Acceptable Organic Bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and Similar. Acceptable inorganic bases include hydroxide of aluminum, calcium hydroxide, potassium hydroxide, carbonate sodium and sodium hydroxide.

Pharmaceutically acceptable salts Preferred are salts formed from acetic acid, acid hydrochloric, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium.

It should be understood that all references to Pharmaceutically acceptable salts include ways of adding solvent (solvates) or crystalline forms (polymorphs) as defined here, of the same acid addition salt.

The terms "pro-drug" and "prodrug", which may be used interchangeably herein, refer to any compound that releases an original active drug according to formula I in vivo when such pro-drug is administered to a mammalian subject. Prodrugs of a compound of formula I are prepared by modification of one or more functional group (s) present in the compound of formula I in which one route of modification (s) may be excision in vivo to release the original compound. Prodrugs include compounds of formula I wherein a hydroxyl, amino, or sulfhydryl group in a compound of Formula I is linked to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (for example, derivatives of acetate, formate, and benzoate), carbamates (e.g., N, N-dimethylaminocarbonyl) of hydroxyl functional groups in compounds of formula I, N-acyl derivatives (eg N-acetyl) N-Mannich bases, Schiff bases and enaminones of functional amino groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of Formula I, and the like, see Bundegaard, H. "Design of Prodrugs" p1-92, Elesevier, New York-Oxford (1985), and the like.

"Protective group" or "protection group" indicates the group that selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another reactive site without protecting the meaning conventionally associated with it in chemical chemistry. synthesis. Certain processes of this invention reside in that the protecting groups block reactive nitrogen and / or oxygen atoms present in the reagents. For example, the term "amino protecting group" and "nitrogen protecting group" are used interchangeably herein and refer to those organic groups that attempt to protect the nitrogen atom from undesirable reactions during synthetic procedures. Examples of nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyl oxycarbonyl, p-nitrobenzyloxycarbonyl, tert -butoxycarbonyl (BOC), and Similar. The experts in the field will understand how to choose a group depending on its ease of elimination and the ability to be consistent with the following reactions.

"Solvates" indicate ways of adding solvent containing both stoichiometric amounts or not stoichiometric solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If he solvent is water the solvate formed is a hydrate, when the Solvent is alcohol, the solvate formed is an alcoholate. The Hydrates are formed by combining one or more water molecules with one of the substances in which water maintains its state molecular as H2O, such combination being capable of forming one or more hydrates.

"Subject" indicates mammals and non-mammals. Mammals indicates any member of the mammal class including,  but not limited to, humans; nonhuman primates such as chimpanzees and other apes and species of monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; animals domestics such as rabbits, dogs, and cats; animals of laboratory including rodents, such as rats, mice, and guinea pigs; and the like Examples of non-mammals They include, but are not limited to, birds, and the like. The term "subject" does not denote a particular age or sex.

"Therapeutically effective amount" indicates an amount of a compound that, when administered to a subject to treat a disease, it is enough to effect said Treatment for the disease. The "amount therapeutically effective "will vary depending on the compound, the state of the disease to be treated, severity or disease to be treated, age and the relative health of the patient, the route and form of administration, the judgment of the practicing doctor or veterinary practitioner, and others factors.

The terms "one defined above" and "those defined above" when we refer to a  variable incorporates by reference to the broad definition of the variable as preferred, more preferred definitions and more preferred, if any.

"Treat" or "treatment" of a disease that includes:

(i) prevent disease, this is to cause the clinical symptoms of the disease do not develop in a subject who may have been exposed or predisposed to the disease, but who does not have experiences or develops symptoms of the disease

(ii) inhibit the disease, that is, stopping the development of the disease or its clinical symptoms, or

(iii) relieving the disease, that is, causing the temporary or permanent regression of the disease or its symptoms clinical.

The terms "treat", "put in contact "and" react "when referring to a reaction Chemistry indicates the addition or mixing of two or more reagents under the appropriate conditions to produce the desired product and / or indicated. It should be appreciated that the reaction produced by the indicated and / or desired product does not have to be necessarily directly from the combination of two reagents that they were initially added, that is, there may be one or more intermediaries that occur in the mixture that ultimately lead to desired and / or indicated product.

In general, the nomenclature used in this request is based on AUTONOM ™ v.4.0, a computerized system of the Beilstein Institute for the generation of nomenclature IUPAC systematic. For convenience, the IUPAC numbering of positions of the representative benzoxazinone compounds described Here is shown in this formula:

18

The invention provides compounds of the General Formula:

19

and pharmaceutically salts acceptable or prodrugs of same,

where:

quad

Y is C or S; preferably Y is C;

quad

m is 1 when Y = C, and m is 2 when Y = S;

quad

n is 1 or 2; preferably n is 1;

quad

p is 0 to 3; preferably p is 1;

quad

q is 1 to 3; preferably q is 2;

quad

Z is - (CR a R b) r - or -SO 2 - where each of R a and R b is independently hydrogen or alkyl; preferably Z is - (CR a R b) r - and preferably R a and R b are hydrogen;

quad

r is from 0 to 2; preferably r is 2;

quad

X is CH or N; preferably X is N;

quad

Each R1 is independently halo, alkyl, haloalkyl, heteroalkyl, alkoxy, cyano, -S (O) s -R c, -C (= O) -NR c R d, -SO 2 -NR c R d, -N (R c) - C (= O) -R d, or -C (= O) R c, where each of R c and R d is independently hydrogen or alkyl; preferably every R1 it is independently halo, alkyl, or alkoxy;

quad

s is 0 to 2;

quad

R2 is aryl or heteroaryl; preferably R2 is aryl, and more preferably optionally phenyl substituted or naphthyl such as 2-halophenyl, 3-halophenyl, 4-halophenyl, naphthylene-2-yl or 4-cyanophenyl;

quad

each of R3 and R4 is independently hydrogen or alkyl, or R 3 and R 4 together with its atom of Shared carbon can form a 3 to 6 cycloalkyl ring members; Y

quad

each of R 5, R 6, R 7, R 8 and R 9 is independently hydrogen or alkyl, or one of R 5 and R 6 together with one of R 7, R 8 and R 9 together with middle atoms can form a ring from 5 to 7 members.

quad

preferably R 5, R 6, R 7, R 8 and R 9 are hydrogen;

In embodiments where any of R1, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R a, R b are alkyl, these are preferably alkyl lower such as (C 1 -C 6) alkyl, and more preferably (C 1 -C 4) alkyl.

It should be understood that the scope of this invention encompasses not only the different isomers that can exist but also to the different mixtures of isomers that They can form. In addition, the scope of the present invention encompasses the solvates and salts of the compounds of Formula I.

In certain embodiments, Z is - (CR a R b) r -, X is N, and q is 2. R 2 in such embodiments may comprise, for example, 2-Halophenyl, 3-Halophenyl, 4-halophenyl, naphthylene-2-yl, 3-cyanophenyl, 4-cyanophenyl, 3-nitrophenyl, 3-aminophenyl, 3-methoxyphenyl, 3-ureaphenyl, or 3-methylsulfonylamino-phenyl. X in several embodiments can be located at position 8 of the Benzoxazinone ring system. In other embodiments X you can  locate in position 6 of the ring system benzoxazinone

In some embodiments of the invention, the Compounds of formula I may be of formula Ia:

twenty

wherein Y, Z, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, m, n, and p are as defined here.

In certain embodiments, the compounds of Formula I may be of formula Ib:

twenty-one

wherein Z, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, n, r and p are as defined here.

In some preferred embodiments present, The compounds of formula I may be of formula Ia1:

         \ vskip1.000000 \ baselineskip
      

22

         \ vskip1.000000 \ baselineskip
      

wherein R 1, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R a, R b n, r and  p are as defined here, and in where:

t is from 0 to 4; preferably t is 1; Y

each of R 10 independently is halo, alkyl, alkoxy, carbamyl, alkylsulfonamido, or cyano; preferably R 10 is halo or alkoxy.

In still other embodiments, the compounds subject may be of formula Ib1

         \ vskip1.000000 \ baselineskip
      

2. 3

         \ vskip1.000000 \ baselineskip
      

wherein R 1, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R a, R b, n, r, p and t are as defined herein. In realizations specific formula Ib1, R1 may be halo, methyl or Methoxy, R 3 and R 4 can independently be hydrogen or methyl together with their shared carbon atom form a group cyclobutyl, R 6, R 7, R 8, R 9, can each be independently hydrogen or methyl, R a and R b each independently it can be hydrogen or methyl, and each R 10 it can be hydrogen, halo, nitro, cyano, amino, urea, methoxy or methanesulfonylamino.

Representative compounds according to the invention are shown in Table 1. Melting point data in Table 1 they are for the hydrochloride salts of the compounds shown unless otherwise indicated.

TABLE 1

24

25

26

27

28

29

30

31

32

33

3. 4

35

Another aspect of the invention provides a composition comprising a therapeutically effective amount of at least one compound of formula I and a pharmaceutically carrier acceptable.

In yet another aspect of the invention it provides a method for the treatment of a disease of the system central nervous (CNS) in a subject comprising a disease in a subject comprising administration to a subject of a therapeutically effective amount of a compound of formula I. The disease may include, for example, psychosis, schizophrenia, manic depressions, neurological disorders, disorders of memory, attention deficit disorder, disease Parkinson's, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's disease.

In yet another aspect of the present invention provides a method for the treatment of a disorder of gastrointestinal tract in a subject that comprises administering to a subject a therapeutically effective amount of a Compound of Formula I.

Another aspect of the present invention provides a method for the production of a compound of formula I.

The compounds of the present invention can be developed using a variety of methods described in the illustrative synthetic reaction schemes shown and described later.

The starting materials and reagents used in the preparation of these compounds are also generally available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those understood in the field following the procedures listed in the references such as Fieser and Fieser's Reagents for Organic Synthesis ; Wiley & Sons: New York, 1991 , Volumes 1-15; Rodd's Chemistry of Carbon Compounds , Elsevier Science Publishers, 1989, Volumes 1-5 &Supplementals; and Organic Reactions , Wiley & Sons: New York, 1991 , Volumes 1-40.

The following synthetic reaction schemes they are merely illustrative of various methods by which you can synthesize the compounds of the present invention, and can be make several modifications of these reaction schemes synthetic and may be suggested by any of the experts on the subject when they have been referred to and shown the revelation contained in this application.

Starting materials and intermediaries Synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional methods, including physical constants and spectral data

Unless otherwise specified, the reactions described here are preferably performed under a inert atmosphere at atmospheric pressure and at a temperature of reaction in the range from -78ºC to about 150ºC, more preferably from about 0 ° C to about 125 ° C, and more preferably and conveniently at room temperature, by example, around 20 ° C.

Scheme A below illustrates the procedure Synthetic used to prepare specific compounds of Formula I where each A independently is halo or other leaving group (such as triflate) and may be the same or different in each case, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Ra, Rb, n, p, q, r and t They are as defined here.

Scheme TO

36

In step 1 of scheme A, an ortho nitrophenol a it is reduced to the corresponding aniline or aminophenol b. This reduction can be done under aqueous conditions, relatively soft, using sodium dithionite or other reducing agents soft.

Cyclization is then carried out in step 2 to provide the compound benzoxazinone from the aminophenol b generated in step 1. Where n is 1, for example, benzoxazinone d is a 2H-1,4-benzoxazin-3 ( 4H) -one, and where n is 2, compound d is a 2,3-dihydro-1,5-benzoxazepin-4 (5H) -one. Cyclization can be obtained by reacting aminophenol b with a 2-halo acid halide c such as chloroacetyl chloride (to provide n = 1 and R3, R4 as hydrogen), 2-chloropropionyl chloride (which provides n = 1 , R3 as methyl and R4 as hydrogen), 3-chloropropionyl chloride (providing n = 2 and R3, R4 as hydrogen), 2-chloroisobutyryl chloride (providing n = 1, R3 as isopropyl and R <3>) 4 as hydrogen), 2-chloro-2-methylpropionyl chloride (providing n = 1 and R 3 and R 4 as methyl), and the like. The formation of benzoxazinones in this way can be achieved under relatively mild polar conditions in the presence of a soft base, as described by Combs et al .; J. Med. Chem .; 33; 380-386 1990 . Cyclization can also be obtained by reacting b with a 2-hydroxy ester under Mitsunobu reaction conditions, as described by Van Hes et al in WO 01/14330.

In step 3, an N-alkylation of the compound benzoxazinone d is carried out by treatment of compound d from Step 2 with a strong base under conditions polar aprotic, dry and reaction with an aryl compound α-haloalkyl e to provide the N-arylalkyl-benzoxazinone compound F. The haloalkyl aryl compound e may comprise, for example, benzyl halide (to provide r = 1 and R a and R b as hydrogen), 3-halo-3-phenylpropane (providing r = 2 and R a, R b as hydrogen), α-methylbenzyl halide (providing r = 1, R a as hydrogen and R b as methyl), or other halides of α-haloalkylphenyl according to the configuration of the desired R a and R b substituents.

The rental of Step 3 can be carried out using α-haloalkyl naphthyl compounds, α-haloalkylbiphenyl or other compounds α-haloalkylaryl compounds. In other embodiment step 3 can be carried out using compounds α-haloalkyl heteroaryl such as α-haloalkylpyridines, α-haloalkylthiophenes, compounds α-haloalkylmethylenedioxyphenyl compounds α-haloalkylethylenedioxyphenyl, and the like. In the case of α-haloalkyl compounds heteroaryl, protective group strategies can be used suitable to avoid alkylation of unwanted heteroatoms during this step. In certain embodiments, the alkylation of the Step 3 can be replaced by an aryl- or heteroaryl-sulfonylation wherein an appropriate arylsulfonyl halide or halide of heteroarylsulfonyl reacts with the ring nitrogen of the benzoxazinone compound d.

An amination reaction then leads to out in Step 4 where the compound N-arylalkyl-benzoxazinone e reacts with a heterocycle containing nitrogen f in the presence of a palladium catalyst to replace the leaving group A- with a heterocyclyl group and provide the compound heterocyclyl-N-arylalkyl-benzoxazinone  Ie In several embodiments, q is 1 such that the compound heterocycle f is a piperazine compound of formula h:

37

and such that the compound heterocyclyl-N-arylalkyl-benzoxazinone of formula Id is of the formula Ie:

38

described above Various alkyl-substituted piperazine compounds are commercially available or can be easily prepared from according to known procedures and can be used in this He passed. The amination of step 4 can be done in both positions 8- and 6- under reaction conditions Similar.

In cases where R 9 is hydrogen, the BOC protection or other appropriate protection strategies will can use to protect the corresponding nitrogen from the ring of compound f. When the BOC protection group is present, the deprotection can be carried out in this step by treatment of the compound heterocyclyl-N-arylalkyl-benzoxazinone  Go with a mild acid solution.

Several variations of the previous procedure are they can suggest for themselves by those understood in the field Once seen this revelation. In some cases, the amination is can perform before the N-alkylation in the position 1. The number, functionality and / or location of the R1 substituent groups can be selected to activate particular positions (that is, any of positions 5 to 8) of the benzoxazinone ring and thus facilitate amination in the selected positions such as sea for realizations specific to the subject compounds.

More specific details for the production of compounds of formula I are described in the examples section later.

The compounds of the invention have affinity selective for 5-HT receptors, including 5-HT6, and as expected are useful in the treatment of certain CNS disorders such as Parkinson's, Huntington's disease, anxiety, depression, depression manic, psychosis, epilepsy, obsessive compulsive disorders, mood swings, migraine, Alzheimer's disease (potentiation of cognitive memory), sleep disorders, disorders of the feeding such as anorexia, bulimia, and obesity, attacks of panic, acatisia, deficit hyperactivity disorder attention (ADHD), attention deficit disorder (ADD), dependence on drugs of abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and other disorders associated with spinal injuries and / or brain injuries such as hydrocephalus. Such compounds are expected to be used in the treatment of certain GI (gastrointestinal) disorders such as  Functional bowel and irritable bowel syndrome.

The pharmacology of the compounds of this invention was determined by procedures recognized in the field. In vitro techniques for determining the affinities of the test compounds in the 5-HT6 receptor in radioligand and functional binding assays are described in Example 4.

The present invention includes compositions Pharmaceuticals comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate of the themselves, together with at least one pharmaceutically acceptable vehicle, and optionally other therapeutic ingredients and / or prophylactic

In general, the compounds of the present invention will be administered in a therapeutically effective amount  by any of the administration modes accepted for agents that serve similar utilities. Dose ranges Appropriate are usually 1-500 mg daily, preferably 1-100 mg daily, and more preferably 1-30 mg daily, depending on several factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and method of administration, the indication to which the administration is directed, and the preferences and experience of the Medical practitioner involved. A normally involved in art of the treatment of such diseases, will be able, without needing experimentation and based on your personal knowledge and the disclosure of this request, to find out an amount therapeutically effective of the compounds of the present invention For a given disease.

In general, the compounds of the present invention will be administered as pharmaceutical formulations including those appropriate for oral use (including oral and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous) or in a form appropriate for administration by inhalation or insufflation. The preferred way of administration is usually oral using a convenient daily dose regimen that It can be adjusted according to the degree of affliction.

A compound or compounds of the present invention, together with one or more conventional adjuvants, vehicles,  or diluents, can be put in the form of compositions Pharmaceuticals and unit doses. The pharmaceutical compositions and unit dose forms may comprise ingredients conventional in conventional proportions, with or without compounds or additional active ingredients, and unit dose forms may contain any appropriate effective amount of active ingredient in proportion to the daily dose range intended to use. Pharmaceutical compositions can be use as solids, such as tablets or filled capsules, semi-solids, powders, release formulations sustained, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled for oral use; or in the form of suppository for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. The formulations contain about one (1) milligram of active ingredient or, more broadly, about 0.01 to around of one hundred (100) milligrams, per tablet, are therefore forms of suitable representative unit doses.

The compounds of the present invention are they can formulate in a wide variety of dosage forms of oral administration Pharmaceutical compositions and forms of dosage may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts of the themselves as active component. The vehicles pharmaceutically Acceptable may also be solids or liquids. The preparations in solid form include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid vehicle it can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, agents tablet disintegrants, or an encapsulating material. In powders, the vehicle is generally a finely divided solid that is a mix with the finely divided active component. In tablets, the active component is usually mixed with the vehicle with the necessary bonding capacity in adequate proportions and compact in the desired shape and size. Powders and tablets preferably contain from one (1) to about seventy (70) percent active compound. Appropriate vehicles include but they are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a wax of low melting point, coconut butter, and the like. The term "preparation" attempts to include the formulation of the compound active with encapsulating materials as a vehicle, providing a capsule in which the active component, with or without excipients, is wrapped by a vehicle, which is in association with it. So similar, cachets and dragees are included. Tablets, powders, Capsules, pills, cachets, and dragees can be solid forms appropriate for oral administration.

Other forms appropriate for oral administration they include preparations in liquid form including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations that are intended to become shortly before use in form preparations liquid Emulsions can be prepared in solutions, by example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, monooleate of sorbitan, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding dyes appropriate, flavoring, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other suspending agents well known. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the component active, dyes, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The compounds of the present invention are can formulate for parenteral administration (for example, by injection, for example bolus injection or continuous infusion) and may present in unit dose forms in ampoules, syringes pre-loaded, small infusion containers volume or in multi-dose containers with the addition of a preservative The compositions can take forms such as suspensions, solutions, or emulsions in vehicles aqueous or oily, for example solutions in polyethylene glycol aqueous. Examples of oily or non-aqueous vehicles, diluents, solvents or vehicles including propylene glycol, polyethylene glycol,  vegetable oils (e.g. olive oil), and esters organic injectables (for example, ethyl oleate), and can contain formulation agents such as preservatives, humectants, emulsifiers or suspensions, stabilizers and / or dispersing agents Alternatively, the active ingredient can be in the form of powders, obtained by aseptic isolation of sterile solid or by lyophilization from the solution for constitution before use with a suitable vehicle, for example, sterile pyrogen free water.

The compounds of the present invention are they can formulate for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. The ointments and creams can, for example, be formulated with a base aqueous or oily with the addition of thickening agents and / or appropriate gelling agents. Lotions can be formulated with a oily or aqueous base and will generally contain one or more agents emulsifiers, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. The  appropriate formulations for topical administration in the mouth include dragees comprising active agents in a base flavored, usually sucrose and acacia or tragacanth; pickups comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes that comprise the active ingredient in a liquid vehicle appropriate.

The compounds of the present invention are can formulate for administration as suppositories. A wax of low melting point, such as a mixture of acid glycerides fatty or coconut butter melts first and the component active is dispersed homogeneously, for example, by stirring. The homogeneous molten mixture then put into size molds appropriate, they are allowed to cool, and solidify.

The compounds of the present invention are They can formulate for vaginal administration. Dispositives intrauterine, tampons, creams, gels, pastes, foams or sprays which contain in addition to the active ingredient other vehicles are known in the field as appropriate.

The compounds of the present invention are They can formulate for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by methods conventional, for example, with a dropper, a pipette or a spray. The formulations can be provided in a form of multidose or single dose. In the last case of a dropper or pipette, this can be obtained administering to the patient an appropriate, predetermined volume of The solution or suspension. In the case of a spray, it can be get for example by methods of an atomizer spray pump weathered

The compounds of the present invention can be formulate by aerosol administration, particularly to the tract respiratory and including intranasal administration. The compound generally it will have a small particle size for example of order of five (5) microns or less. Such particle size is can be obtained by methods known in the field, for example by micronization The active ingredient is provided in a pack pressurized with a suitable propellant such as chlorofluorocarbonates (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon or other appropriate gas. The spray can also contain conveniently a surfactant such as lecithin. The dose of Drug can be controlled by a weathered valve. Alternatively the active ingredients can be provided in a form of dry powder, for example a mixture of powders of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powdered vehicle will form a gel in the nasal cavity The powder composition may be presented in the form unit dose for example in the form of capsules or cartridges of for example, jelly packs or blisters from which the powder It can be administered by an inhaler methods.

When desired, formulations can be prepare with enteric covers adapted for administration controlled or sustained active ingredient. For example, the Compounds of the present invention can be formulated in transdermal or subcutaneous distribution devices. These distribution systems are advantageous when the release Sustained compound is necessary and when compliance with Treatment regimen patient is crucial. The compounds in transdermal distribution systems are linked frequently to a solid adhesive support to the skin. The compound of interest can also be combined with an enhancer of the penetration, for example, Azona (1-dodecylazacycloheptan-2-one). Sustained release distribution systems are inserted subcutaneously in a subdermal layer by surgery or injection. Subdermal implants encapsulate the compound in a membrane lipid soluble, for example, silicone rubber, or a polymer biodegradable, for example, polylactic acid.

The pharmaceutical preparations are preferably in a unit dose form. In that way, the preparation is subdivided into unit doses containing appropriate amounts of the active component. The dosage form unitary can be a packaged preparation, packaging contains discrete amounts of preparation, such as tablets, capsules, and powders in vials or ampoules. Also, the dosage form unitary can be a capsule, tablet, cachet, or dragee in case same, or it can be an appropriate number of any of these packaging forms.

Other appropriate pharmaceutical vehicles and their formulations are described in Remington: The Science and Practice of Pharmacy 1995 , edited by EW Martin, Mack Publishing Company, 19t edition, Easton, Pennsilvania. Representative pharmaceutical formulations contain a compound of the present invention as described in Examples 6-12.

Examples

The following preparations and examples are given to allow those in the field to understand more clearly and put into practice the present invention. They are not due consider as a limitation of the scope of the invention, but merely as illustrative and representative of it.

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Example one

Hydrochloride 4-benzyl-8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one, Salt

The synthetic procedures described in this Example were carried out according to the process shown in the Scheme B wherein R 1 and R 10 are as defined here.

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Scheme B

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39

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He passed one

2-amino-6-bromo-fluorophenol

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40

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Sodium dithionite (58 g, 335 mmol) was dissolved in warm water (300 mL) and slowly added to a solution of 6-Bromo-4-fluoro-2-nitrophenol (11.8 g, 50 mmol) in 250 mL of ethanol heated in a steam bath. The reaction mixture turned dark orange to yellow pale. The suspension is diluted with water until a light yellow solution. The partial concentration in a Rotary evaporator includes induced crystallization. The mixture is then cooled to room temperature and crystals formed. Filtration and drying provided the title compound as white solid (5.04 g, 49% yield). MS 207 (M + H) +.

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He passed 2

8-Bromo-6-methoxy-4 H -benzo [1,4] oxazin-3-one

41

The reaction in this example was performed following procedures similar to those provided in the literature. See for example, Combs, Donald W .; Rampulla, Marianne S .; Bell, Stanlei C .; Klaubert, Dieter H .; Tobia, Alfonso J .; et al .; J. Med. Chem .; 33; 1990; 380-386.

A saturated solution of NaHCO 3 in water (20 mL) was added to a solution of 2-amino-6-bromo-4-methoxyphenol  (9.8 g, 45 mmol) in 300 mL of 2-butanone. He Chloroacetyl Chloride (6.1 g, 54 mmol) was added dropwise to room temperature, and the mixture was refluxed while stirred for 2 hours. After cooling to room temperature, it water and ethyl acetate were added and the organic phase was separated and dried over Na2SO4, filtered, concentrated to give a solid pale brown. Recrystallization from EtOAc gave 2.2 g of the title compound as colored solids pale red The stock solution was chromatographed on silica gel. using EtOAC / Hex (1: 4) to give another 2.6 g of red solids pale. Mp = 236.1-237.5 ° C.

The following compounds were prepared from a similar mode:

8-Bromo-4 H -benzo [1,4] oxazin-3-one, Mp = 243.5-244.9 ° C

8-Bromo-6-fluoro-4 H -benzo [1,4] oxazin-3-one, MS 247 (M + H) +.

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He passed 3

4-Benzyl-8-bromo-4 H -benzo [1,4] oxazin-3-one

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42

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To a solution of 8-bromo-4 H -benzo [1,4] oxazin-3-one (343 mg, 1.5 mmol) in 10 ml of anhydrous dimethylformamide was added sodium hydride (120 mg of a 60% suspension in mineral oil, 3.0 mmol) in portions at 0 ° C. The solution was stirred with a magnetic stirrer at 0 ° C for 20 minutes, at the time when the initial gas evolution ended. Benzyl bromide (0.22 ml, 1.8 mmol) was added in one portion and the reaction mixture was stirred at 0 ° C for 30 minutes. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The aqueous phase was extracted with ethyl acetate (2 x 25 ml) and the combined organic fractions washed with water (2 x 25 ml) and brine (2 x 25 ml). After drying over MgSO4, the organic fraction was concentrated in vacuo and the resulting brown residue was purified by flash chromatography (5% -15% Ethyl acetate / Hexane in 30 minutes) to give 402 mg of 4-benzyl-8 -bromo-4H-benzo [1,4] oxazin-3-one as a yellow solid (84%). MS: 318 (M + H) +.

The following compounds were prepared from a similar way starting from the appropriate bromobenzo [1,4] oxazinone and various bromides of arylalkyl and arylalkyl chlorides, which are both commercially available or known in the literature:

4-Benzyl-8-bromo-6-methyl-4H-benzo [1,4] oxazin-3-one, MS (M + H) +: 334.0.

4-Benzyl-8-bromo-6-methoxy-4 H -benzo [1,4] oxazin-3-one, MS (M + H) +: 350.0.

8-Bromo-4- (2-fluoro-benzyl) -6-methoxy-4 H -benzo [1,4] -oxazin-3-one, MS (M + H) +: 367.9.

8-Bromo-4- (2-chloro-benzyl) -6-methoxy-4 H -benzo [1,4] -oxazin-3-one, 1 H NMR (CDCl 3, 300 M Hz) δ: 3.66 (s, 3H), 4.79 (s, 2H), 5.22 (s, 2H), 6.29 (d, 1H, J = 2.83 Hz), 6.74 ( d, 1H, J = 2.83 Hz), 7.00 (m, 1H), 7.20 (m, 2H), 7.42 (m, 1H).

8-Bromo-4- (3-chloro-benzyl) -6-methoxy-4 H -benzo [1,4] -oxazin-3-one, MS (M + H) +: 382.9

4-Benzyl-8-bromo-6-fluoro-4 H -benzo [1,4] oxazin-3-one, MS (M + H) +: 335.0

8-Bromo-4- (2-fluoro-benzyl) -4 H -benzo [1,4] oxazin-3-one, MS (M + H) +: 338.1

8-Bromo-4- (4-fluoro-benzyl) -4 H -benzo [1,4] oxazin-3-one, MS (M + H) +: 334.9

8-Bromo-4- (4-chloro-benzyl) -4 H -benzo [1,4] oxazin-3-one, MS (M + H) +: 354.0

8-Bromo-6-fluoro-4- (4-fluoro-benzyl) -4 H -benzo [1,4] -oxazin-3-one, MS (M + H) +: 352.9

8-Bromo-6-fluoro-4- (2-fluoro-benzyl) -4 H -benzo [1,4] -oxazin-3-one, 1 H NMR (CDCl 3, 300 M Hz) δ: 4.79 (s, 2H), 5.18 (s, 2H), 6.63 (dd, 1H, J = 2.64 Hz, 9.42 Hz), 6.96 (dd, 1H, J = 2.83 Hz, 7.73 Hz), 7.10 (m, 3H), 7.28 (m, 1H).

8-Bromo-6-fluoro-4- (2-chloro-benzyl) -4 H -benzo [1,4] -oxazin-3-one, MS (M + H) +: 371.0

8-Bromo-6-fluoro-4- (4-chloro-benzyl) -4 H -benzo [1,4] -oxazin-3-one, MS (M + H) +: 370.9

8-Bromo-6-fluoro-4-naphthalen-2-ylmethyl-4 H -benzo [1,4] -oxazin-3-one, MS (M + H) +: 384.9.

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He passed 4

4-benzyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt

43

A solution of 4-benzyl-8-bromo-4 H -benzo [1,4] oxazin-3-one (402 mg, 1.26 mmol) and 1-Boc- piperazine (285 mg, 1.53 mmol) in 3 mL of toluene was added to the mixture of Pd2 (dba) 3 (28 mg, 0.03 mmol), BINAP (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl) (41 mg, 0.066 mmol), NaO t- Bu (175 mg, 1.82 mmol). With stirring, the solution was heated at 95 ° C-100 ° C for 1 hour and allowed to cool to room temperature. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was washed with water (2 x 15 ml) and brine (1 x 15 ml). After drying over MgSO4, the organic fraction was concentrated in vacuo and resulted in a brown residue that was purified by flash chromatography (10% -40% ethyl acetate / hexane in 30 minutes) to give 168 mg of the compound boc- protected in the form of a yellow solid (32%). Tert-Butyl 4- (4-Benzyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -piperazine-1-carboxylate (0.168 g., 0.4 mmol) was dissolved in 4 ml of ethanol. To this solution was added a 2M hydrochloric acid ethanol solution (3 ml.). The mixture was heated at 100 ° C (steam bath) for 20 minutes, at the time crystalline solids formed. The solution was allowed to cool to room temperature and 0.115 g of 4-benzyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt was collected as a pale yellow after filtration and dried in a vacuum oven. MS: 324 (M + H) +, mp = 235.9-236.2 ° C.

The following compounds were prepared from a similar way starting from the bromobenzo [1,4] oxazinones appropriately replaced:

4-benzyl-6-methyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt, MS: (M + H) + 338, mp =
256.8-263.9 ° C.

4-benzyl-6-methoxy-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one salt hydrochloride, MS: (M + H) + 354.

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4- (2-Fluoro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt, MS: (M + H) + 372, mp = 268.1-271.0 ° C.

4- (2-Chloro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt, MS: (M + H) + 388, mp = 286.9-288.9 ° C.

4- (3-Chloro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt, MS: (M + H) + 388, mp = 55.2-58.8 ° C.

4-benzyl-6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt, MS: (M + H) + 342, mp = 268.2-268.3 ° C.

4- (2-Fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt, MS: (M + H) + 342, mp = 236.0-244.5 ° C.

4- (3-Fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one hydrochloride salt, mp = 231.7-236.5 ° C

4- (4-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one hydrochloride salt, MS: (M + H) + 342, mp = 240.0-242.4 ° C.

4- (4-Chloro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one hydrochloride salt, MS: (M + H) + 358, mp = 250.9-253.8 ° C.

4- (4-fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt, MS: (M + H) + 360, mp => 300 ° C.

4- (2-Fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt, MS: (M + H) + 360, mp = 282.0-282.9 ° C.

4- (2-Chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt, MS: (M + H) + 376, mp => 300 ° C.

4- (4-Chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt, MS: (M + H) + 376, mp = 271.7-272.4 ° C.

6-fluoro-4-naphthalen-2-ylmethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one hydrochloride salt, MS: (M + H) + 392, mp = 255.8-256.1 ° C.

4- (3-Methoxy-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one, hydrochloride salt MS: (M + H) + 354.

4- (3-Nitro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one, hydrochloride salt MS: (M + H) + 369.

4- (3-Amino-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one, hydrochloride salt MS: (M + H) + 339.

3- (3-Oxo-8-piperazin-1-yl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzonitrile, hydrochloride salt. MS: (M + H) +
349.

4- (3-Oxo-8-piperazin-1-yl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzonitrile, hydrochloride salt. MS: (M + H) +
349.

N- [3- (3-Oxo-8-piperazin-1-yl-2,3-dihydro-benzo [1,4] -oxazin-4-ylmethyl) -phenyl] -methanesulfonamide, hydrochloride salt MS: (M + H) + 417.

[3- (3-Oxo-8-piperazin-1-yl-2,3-dihydro-benzo [1,4] -oxa-zin-4-ylmethyl) -phenyl] -urea, hydrochloride salt. MS: (M + H) +
382

4- (3-Chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one, hydrochloride salt mp = 260.2-263.1 ° C.

Using the above procedure, but with 4-bromomethyl pyridine in step 3 instead of benzyl bromide, the 8-piperazin-1-yl-4-pyridin-4-ylmethyl-4H-benzo [1,4] oxazin-3-one, hydrochloride salt MS: (M + H) + 325.

Using the above procedure, but with 1-Bromoethyl benzene in step 3 instead of bromide of benzyl, the 4- (1-Phenyl-ethyl) -8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one, hydrochloride salt MS: (M + H) + 338.

Using the above procedure, but in the step 4 replacing the boc-protected piperazine with 3,5-dimethyl piperazine boc-protected provided the 4-Benzyl-8- (3,5-dimethyl-piperazin-1-yl) -4H-benzo [1,4] oxazin-3-one, hydrochloride salt MS: (M + H) + 352. Similarly, using 3,3-dimethyl piperazine boc-protected in step 4 provided 4-Benzyl-8- (3,3-dimethyl-piperazin-1-yl) -4H-benzo- [1,4] oxazin-3-one, hydrochloride salt MS: (M + H) + 352.

Similarly, but using 2-amino-6-bromo-4-methoxyphenol in step 2 to provide 6-bromo-4 H -benzo [1,4] oxazin-3-one in step 3, the following were prepared compounds:

4-Benzyl-6-piperazin-1-yl-4 H -benzo [1,4] oxazin-3-one, hydrochloride salt. MS: (M + H) + 324.

4- (4-Fluoro-benzyl) -6-piperazin-1-yl-4 H -benzo [1,4] oxazin-3-one, hydrochloride salt, MS: (M + H) + 342.

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Example 2

4-Benzyl-6-methyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1,4] oxazin-3-one

44

To a solution of 4-Benzyl-6-methyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one (140 mg, 0.42 mmol) in CH 2 Cl 2 (5 ml) of Example 1 is formaldehyde added (37% solution in water, 50 µL, 0.67 mmol) and NaBH (OAc) 3. The solution was stirred with a stirrer. magnetic at room temperature for 2 hours, and then it partitioned between CH 2 Cl 2 (20 ml) and a saturated solution NaHCO 3 (20 ml). The aqueous phase was extracted with CH 2 Cl 2 (2 x 20 ml). After drying in MgSO4, the organic fraction was concentrated in vacuo to give 4-Benzyl-6-methyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1,4] oxazin-3-one in the form of a yellow solid. (140 mg, 95%) MS: (M + H) + 352.

Similarly it was prepared from 4-benzyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one the 4-benzyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1,4] oxazin-3-one:  MS: (M + H) + 338.

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Example 3

4-Benzyl-2,2-dimethyl-8-piperazin-1-yl-4 H -benzo [1,4] oxazin-3-one

The synthetic procedures described in this Example were carried out according to the process shown in the Scheme C wherein R 1 and R 10 are as defined here.

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Scheme C

46

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He passed one

2-Bromo-N- (3-bromo-2-hydroxy-phenyl) -2-methyl-propionamide

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Four. Five

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Pyridine (1.8 ml, 22.3 mmol) was added to a solution of 2-amino-6-bromo-phenol (4.198 g, 22.3 mmol) in dry CH2Cl2 (200 ml). Mix cooled on ice and then a solution of slowly added bromide of 2-Bromo-2-methyl-propionyl  (2.8 ml, 22.6 mmol). The mixture was stirred at room temperature. for an hour and put in CH2Cl2 and water. The phase Organic was washed with water, dried and concentrated in vacuo to provide the 2-Bromo-N- (3-bromo-2-hydroxy-phenyl) -2-methyl-propionamide  gross, which was used directly in step 2.

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He passed 2

8-Bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one

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47

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The 2-Bromo-N- (3-bromo-2-hydroxy-phenyl) -2-methyl-pro-pionamide from step 1 it was dissolved in DMF (200 ml), and the DMF solution was added to K 2 CO 3 (6.3 g, 45.58 mmol). The mixture was heated overnight at 150 ° C, then cooled and put in a water / ethyl acetate mixture. The organic fraction was washed with brine. After drying over MgSO4, the organic fraction was dried under vacuum and the resulting brown residue was purified by flash chromatography to give 8-Bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one in the form of a white solid (84.6%). MS: (M-H) - 256.

Similarly it was prepared 8-Bromo-6-fluoro-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one: MS: (M-H) - 272.

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He passed 3

4-Benzyl-8-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one

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48

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The N-benzylation of 8-Bromo-2,2-dimethyl-4H-benzo- [1,4] oxazin-3-one in this step it was carried out using the procedure of step 3 of the Example 1 as described above, to provide 4-benzyl-8-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one.  MS: (M + H) 347.

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He passed 4

4-Benzyl-2,2-dimethyl-8-piperazin-1-yl-4 H -benzo [1,4] -oxazin-3-one

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49

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The amination and subsequent deprotection of 4-benzyl-8-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one in this step was carried out using the procedure of step 4 of Example 1 such as described above to provide 4-Benzyl-2,2-dimethyl-8-piperazin-1-yl-4 H -benzo [1,4] -oxazin-3-one, hydrochloride salt.

Using the procedure of Example 3 using the appropriately substituted benzyl bromides, also They prepared the following compounds:

4- (4-Fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one, hydrochloride salt MS: (M + H) 370.

4- (3-Fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-on, hydrochloride salt MS: (M + H) 370.

4- (3-Chloro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one, hydrochloride salt MS: (M + H) 386:

4- (4-Chloro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one, hydrochloride salt MS: (M + H) 386.

4-Benzyl-6-fluoro-2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one, hydrochloride salt MS: (M + H) 370.

4- (4-Chloro-benzyl) -6-fluoro-2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one, hydrochloride salt MS: (M + H) 405.

6-Fluoro-4- (3-fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one, hydrochloride salt. MS:
(M + H) 389.

6-Fluoro-4- (2-fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one, hydrochloride salt. MS:
(M + H) 389.

6-Fluoro-4- (4-fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one, hydrochloride salt. MS:
(M + H) 389.

4- (3-Chloro-benzyl) -6-fluoro-2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one, hydrochloride salt MS: (M + H) 405.

Using the above procedure, but replacing 2-Bromo-2-methyl-propionylbromide in step 1 with (R) - and (S) - 2-Bromo-propionylbromide, They provided the following compounds:

(R) -4-Benzyl-2-methyl-8-piperazin-1-yl-4 H -benzo [1,4] -oxazin-3-one, hydrochloride salt. MS: (M + H) 338: and

(S) -4-Benzyl-2-methyl-8-piperazin-1-yl-4 H -benzo [1,4] -oxazin-3-one, hydrochloride salt. MS: (M + H) 338.

Similarly, but replacing 2-bromo-2-methyl-propionylbromide in step 1 with (1-bromo-cyclobutyl) -acetyl bromide, 4-Benzyl-2,2-spiro-cyclobutan-8-piperazin-1-yl -4 H -benzo [1,4] oxazin-3-one, hydrochloride salt was prepared. MS: (M + H) 363.

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Example 4

1-Benzyl-5-piperazin-1-yl-1H-benzo [1,3,4] oxathiazine 2,2-dioxide

The synthetic procedures described in this Example were carried out according to the procedure shown in scheme D.

Scheme D

fifty

He passed one

4- (2-benzyloxy-3-nitro-phenyl) -piperazine-1-carboxylate of tert-butyl

51

A round bottom flask was added 2-benzyloxy-1-bromo-3-nitro-benzene (9.24 g., 30 mmol), piperazine-1-carboxylic acid tert-butyl (6.15 g., 33 mmol), tris (dibenzylidenacetone) dipaladium (0) (1.09 g., 1.2 mmol), and rac-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl  (1.86 g., 3 mmol). The bottle was purged with nitrogen, charged with toluene (60 mL) and heated at 90 ° C for 2.5 hours. The mixture of reaction was filtered through celite, and the celite was washed with of 100 mL ethyl acetate. The filtrate was concentrated in vacuo and the resulting residue was purified by flash chromatography (30% to 50% of ethyl acetate in hexanes) to deliver 870 mg. of the 4- (2-benzyloxy-3-nitro-phenyl) -piperazine-1-carboxylate  of tert-butyl as a red oil (9%). (M + H) + = 324.

He passed 2

4- (3-amino-2-hydroxy-phenyl) -piperazine-1-carboxylate of tert-butyl

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52

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To a flask containing 10 mg of platinum dispersed in charcoal (5%) the 4- (2-benzyloxy-3-nitro-phenyl) -piperazine-1-carboxylate  of tert-butyl (680 mg, 1.65 mmol) and ethanol (5 mL) The system was purged with hydrogen by alternative application of vacuum and hydrogen gas. The resulting suspension was stirred at room temperature for 2 hours and then filtered through of celite. The celite was rinsed with 45 ml of ethyl acetate, and the organic solutions were combined and concentrated in vacuo to give 280 mg of the 4- (3-amino-2-hydroxy-phenyl) -piperazine-1-carboxylate  of tert-butyl as a brown foam (58%). (M + H) + = 294.

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He passed 3

4- (3-Chloromethanesulfonylamino-2-hydroxy-phenyl) -piperazine-1-carboxylate of tert-butyl

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53

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It dissolved in a round bottom flask, 4- (3-amino-2-hydroxy-phenyl) -piperazine-1-carboxylate of tert-butyl (293 mg., 1 mmol) in dry THF (3 mL) low nitrogen While stirring, chlorine chloride was added dropwise chloro-methanesulfonyl (149 mg., 1 mmol) for 10 minutes and the solution was stirred 30 minutes. The pyridine (0.121 mL., 1.5 mmol) dropwise over 5 minutes and the solution was stirred for 18 hours. The reaction mixture was diluted. with 40 mL Et2O and washed with 40 mL of 10% aqueous HCl, 50 mL of water, and 50 mL of brine. The organic fraction was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20% to 40% EtOAc in hexane) to give 190 mg of 4- (3-Chloromethane-sulfonylamino-2-hydroxy-phenyl) -piperazine-1-carboxylate  of tert-butyl as an amber oil (45%). (M-H) - = 404.

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He passed 4

4- (1-Benzyl-2,2-dioxo-2,3-dihydro-1 H -benzo [4,2,1] -oxathiazin-5-yl) -piperazine-1-carboxylate of tert-butyl

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54

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To a bottle containing 7 mL methanol was added he 4- (3-Chloromethanesulfonylamino-2-hydroxy-phenyl) -piperazine-1-carboxylate  of tert-butyl (190 mg., 0.471 mmol) and carbonate of potassium (195 mg, 1.4 mmol). The suspension was refluxed. for two hours under nitrogen and allowed to cool to temperature ambient. To the reaction mixture was added benzyl bromide (0.083 mL, 0.7 mmol) and potassium carbonate (87 mg., 0.7 mmol), and the The reaction was stirred at room temperature for 4 hours. Mix The reaction was concentrated in vacuo and the resulting crude solid was dissolved in ethyl acetate. The solution was washed with 50 mL of water and 50 mL of brine, and the ethyl acetate was removed in vacuo. He resulting residue was purified by flash chromatography to give 57 mg of 4- (1-Benzyl-2,2-dioxo-2,3-dihydro-1 H -benzo [4,2,1] oxathiazin-5-yl) -piperazine-1-carboxylate of tert-butyl as a light purple oil (26%). (M + H) + = 460.

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He passed 5

1-Benzyl-5-piperazin-1-yl-1H-benzo [4,2,1] oxathiazine 2,2-hydrochloride dioxide

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55

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4- (1-Benzyl-2,2-dioxo-2,3-dihydro-1 H -benzo [4,2,1] oxa-thiazin-5-yl) -piperazine-1-carboxylate of tert-butyl was dissolved in 1 mL of methanol and added 1 mL of 2N ethanolic HCl. The solution was heated to 100 ° C. for 30 minutes, at that time approximately 2 were added mL of Et2O. Cooling at room temperature, 30 mg of 2,2-hydrochloride dioxide 1-benzyl-5-piperazin-1-yl-1H-benzo [4,2,1] -oxathiazine they precipitated as a white solid (61%). (M + H) + = 360

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Example 5

Formulations

Pharmaceutical preparations for distributed by several routes were formulated as shown in the following Tables. "Active ingredient" or "compound active "as used in the Tables refers to one or more Compounds of Formula I.

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Composition for Oral Administration

56

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The ingredients were mixed and disposed in capsules containing about 100 mg each; a capsule It would approximate the total daily dose.

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Composition for Oral Administration

57

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The ingredients were combined and granulated using a solvent such as methanol. The formulation is then Dry and transform into tablets (containing approximately 20 mg of the active compound) with a compressing machine adequate.

Composition for Oral Administration

59

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The ingredients were mixed to form a suspension for oral administration.

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Parenteral Formulation

60

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The active ingredient was dissolved in one portion of water for injections. A sufficient amount of sodium chloride with stirring to make the solution isotonic. The solution was developed to reach the weight with the rest of the water for injections, it was filtered through a 0.2 membrane filter microns and were packaged under sterile conditions.

Formulation of Suppositories

61

The ingredients were melted together and mixed in a steam bath, and poured into molds that contain 2.5 g of total weight

Topical formulation

62

All ingredients, except water, are combined and heated at 60 ° C with stirring. An amount sufficient water of around 60 ° C was added with stirring energetic to emulsify the ingredients, and then water was added c.s.p up to about 100 g.

Nasal Spray Formulation

Several aqueous suspensions containing about 0.025-0.5 percent compound Active were prepared as nasal spray formulations. The formulations optionally contain active ingredients such such as microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, and the like. Hydrochloric acid can be added to adjust the pH. Nasal spray formulations can be released via a weathered nasal spray measuring pump normally releasing around 50-100 formulation microliters per operation. An agenda of Typical daily dosage is 2-4 beats every 4-12 hours.

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Example 6

Radioligand binding studies

This example illustrates in vitro aradioligand binding studies of Compounds of Formula I.

The binding activity of compounds of this invention in vitro was determined as follows. Duplicate ligand affinity determinations were performed by competition of [3 H] LSD binding on cell membranes derived from stable HEK293 cells expressing the recombinant human 5-HT6 receptor.

All determinations were made in one assay buffer containing 50 mM Tris-HCl, 10 mM MgSO4, 0.5 mM EDTA, 1 mM ascorbic acid, pH 7.4 a 37 ° C, in a reaction volume of 250 microliters. The tubes of assay containing [3 H] LSD (5 nM), competition ligand, and the membrane was incubated in a water bath with stirring during 60 min. at 37 ° C, they were filtered on Packard plates GF-B (pre-soaked with 0.3% PEI) using a 96-well Packard cell cultivator and washed 3 times with 50 mM Tris-HCl in cold ice. Be determined the [3 H] LSD binding as radioactive counts by minute using Packard TopCount.

The displacement of [3H] LSD of the binding sites were quantified by adjusting the binding data - concentration to a logistic equation of 4 parameters:

63

where Hill is the Hill slope, [ligand] is the concentration of the competition radioligand and IC 50 is the concentration of radioligand that produces half of the maximum specific radioligand binding. The specific binding window is the difference between Bmax and the baseline parameters.

Using the processes in this Example, the compounds of Formula I were tested and found to be selective 5-HT6 antagonists. They are shown in the Table 2 representative affinity values for the compounds of the invention.

TABLE 2

64

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Example 7

Knowledge Empowerment

The properties of enhancing the knowledge of the compounds of the invention may be in an animal knowledge model: the object recognition task model. 4-month-old male Wistar rats (Charles River, The Netherlands) were used. The compounds were prepared daily and dissolved in physiological serum and tested at three doses. Administration is always carried out by ip (injection volume 1 ml / kg) 60 minutes before T1. Scopolamine hydrobromide was injected 30 minutes after injecting the compound. Two equal test groups of 24 rats were made and tested by two experimenters. The trial order of the doses was determined by randomization. The experiments were carried out using a double blind protocol. All rats were treated once with each dose condition. The object recognition test was carried out as described by Ennaceur, A., Delacour, J., 1988, A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res . 31 , 47-59.

While the present invention has been described with reference to the specific embodiments thereof, it must be understand by those experts in the field that can be done several changes and equivalents can be substituted without departing of the true spirit and objective of the invention. In addition, many modifications can be made to adapt to a situation particular, material, composition of matter, process, step of process or steps, to the spirit of the objective and scope of the present invention. All these modifications try to be within the scope of the claims indexed below.

Claims (17)

1. A compound of the formula: 65 or a salt or pharmaceutically acceptable pro-drug from same, where:

quad

Y is C or S;

quad

m is 1 when Y is C and m is 2 when Y is S;

quad

n is 1 or 2;

quad

p is 0 to 3;

quad

q is 1 to 3;

quad

Z is - (CR a R b) r - or -SO 2 -, where each R a and R b are hydrogen or alkyl independently;

quad

r is from 0 to 2;

quad

X is CH or N;

quad

each R1 is independently halogen, alkyl, haloalkyl, heteroalkyl, alkoxy, cyano, -S (O) s -R c, -C (= O) -NR c R d, -SO 2 -NR c R d, -N (R c) - C (= O) -R d, or -C (= O) -R c, where each R c and R d is independently hydrogen or alkyl;

quad

s is 0 to 2;

R2 is phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxidiphenyl, diphenyl, methylene diphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxilyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperidinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triacinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, acepinyl, diacepinyl or acridinyl, optionally independently substituted with one to four substituents chosen from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, -COR, - (CR'R '') k -COOR '' ', or - (CR'R '') k -CONR '' 'R' '' ',

quad

where k is an integer from 0 to 5,

quad

where R is hydrogen, alkyl, phenyl or phenylalkyl,

quad

where R 'and R' 'are independently hydrogen or I rent,

quad

where R '' 'and R' '' 'are, independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl;

quad

optionally substituted;

each of R 3 and R 4 is independently hydrogen or alkyl, or R 3 and R 4 together with their shared carbons they can form a cycloalkyl ring from 3 to 6 members; Y each of R 5, R 6, R 7, R 8 and R 9 are independently hydrogen or alkyl, or one of R 5 and R 6 together with one of R 7, R 8 and R 9 and the Middle atoms can form a 5 to 7 member ring. 2. A compound of claim 1, in where R2 is phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxidiphenyl, diphenyl, methylene diphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxilyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperidinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triacinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, acepinyl, diacepinyl or acridinyl,

quad

optionally substituted by (R 10) t, where

quad

t has a value of 0 to 4;

quad

each R 10 is independently hydrogen, halo, alkyl, alkoxy, cyano, nitro, amino, urea or ethanesulfonylamino.

3. A compound of dividend 1 or 2, in where

n

is 1;

p

It has a value from 0 to 1;

that

is 2;

Z

is - (CR a R b) r, where each R a and R b is independently hydrogen or I rent;

r

is 1;

X

is N; Y

each of R 5, R 6, R 7, R 8 and R 9 is independently hydrogen or alkyl. 4. The compound of claim 3, in where each of R a and R b is independently methyl or hydrogen; R2 is phenyl optionally substituted, naphthyl or pyridine optionally replaced; each of R3 and R4 is independently methyl or hydrogen, or R 3 and R 4 together form a ring cyclobutyl 5. The compound of claim 3, in where R2 is 2-halophenyl, 3-halophenyl, 4-halophenyl, naphthylene-2-yl, 3-cyanophenyl, 4-cyanophenyl, 3-nitrophenyl, 3-amino-phenyl, 3-methoxyphenyl, 3-ureaphenyl, 3-methylsulfonylamino-phenyl or pyridine-4-yl. 6. The compound of claim 1, in where said compound is of formula 66 or a salt or pharmaceutically acceptable pro-drug thereof, wherein Z, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, n, and p are as defined in the claim one. 7. The compound of claim 1, wherein said compound is of formula

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67

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or a salt or pharmaceutically acceptable pro-drug thereof, wherein Z, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, n, and p are as defined in the claim one. 8. The compound of claim 1, in where said compound is of formula

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68

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or a salt or pharmaceutically acceptable pro-drug thereof, wherein R 1, R 3, R 4, R 5, R 6, R 7, R 8, R 9 R a, R b n, r and p are as defined in the claim 1, and wherein t is from 0 to 4; and every R 10 independently it is hydrogen, halo alkyl, alkoxy, cyano, nitro, amino, urea or ethanesulfonylamino.

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9. The compound of claim 1, in where said compound is of formula

           \ vskip1.000000 \ baselineskip
        

69

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or a salt or pharmaceutically acceptable pro-drug thereof, wherein R 1, R 3, R 4, R 5, R 6, R 7, R 8, R 9 R a, R b n, r and p are as defined in the claim 1, and wherein t is from 0 to 4; and every R 10 independently it is hydrogen, halo alkyl, alkoxy, cyano, nitro, amino, urea or ethanesulfonylamino. 10. The compound of claim 1 to 8, in where said compound is selected from: 4-benzyl-6-methyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4-benzyl-6-methoxy-8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one; 4- (2-Fluoro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4- (2-Chloro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4- (3-Chloro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4-benzyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4-benzyl-6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one; 4- (2-Fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one; 4- (4-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one; 4- (4-Chloro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one; 4- (4-fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-beno [1,4] oxazin-3-one; 4- (2-Fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4- (2-Chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4- (4-Chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 6-fluoro-4-naphthalen-2-ylmethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4- (3-Chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 3- (3-oxo-8-piperazin-1-yl-2,3-dihydro-benzo [1,4] -oxazin-4-ylmethyl) -benzonitrile; 4- (3-Fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one; 4-benzyl-2,2-dimethyl-8-piperazin-1-yl-4 H -benzo [1,4] -oxazin-3-one; (R) -4-Benzyl-2-methyl-8-piperazin-1-yl-4 H -benzo [1,4] -oxazin-3-one; 4-Benzyl-6-piperazin-1-yl-4 H -benzo [1,4] oxazin-3-one; 4- (4-Fluoro-benzyl) -6-piperazin-1-yl-4 H -benzo [1,4] -oxazin-3-one; (S) -4-Benzyl-2-methyl-8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one; 8-Piperazin-1-yl-4-pyridin-4-ylmethyl-4H-benzo [1,4] -oxazin-3-one; 4-Benzyl-6-methyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1,4] oxazin-3-one; 4-Benzyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1,4] -oxazin-3-one; 4- (1-Phenyl-ethyl) -8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4- (3-Methoxy-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one; 4- (3-Nitro-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one; 4- (3-Amino-benzyl) -8-piperazin-1-yl-4H-benzo [1,4] -oxazin-3-one; 3- (3-Oxo-8-piperazin-1-yl-2,3-dihydro-benzo [1,4] -oxazin-4-ylmethyl) -benzonitrile; N- [3- (3-Oxo-8-piperazin-1-yl-2,3-dihydro-benzo [1,4] -oxazin-4-ylmethyl) -phenyl] -methanesulfonamide; 4- (4-Fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4- (3-Fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; [3- (3-Oxo-8-piperazin-1-yl-2,3-dihydro-benzo [1,4] -oxazin-4-ylmethyl) -phenyl] -urea; 4- (3-Chloro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4-Benzyl-8- (3,5-dimethyl-piperazin-1-yl) -4H-benzo [1,4] -oxazin-3-one; 4- (4-Chloro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4-Benzyl-6-fluoro-2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4- (4-Chloro-benzyl) -6-fluoro-2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 6-Fluoro-4- (3-fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 6-Fluoro-4- (2-fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 6-Fluoro-4- (4-fluoro-benzyl) -2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one 4- (3-Chloro-benzyl) -6-fluoro-2,2-dimethyl-8-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one; 4-Benzyl-8- (3,3-dimethyl-piperazin-1-yl) -4H-benzo [1,4] -oxazin-3-one; 1-Benzyl-5-piperazin-1-yl-1H-benzo [1,3,4] oxathiazine 2,2-dioxide; Y 4-Benzyl-2,2-spiro-cyclobutan-8-piperazin-1-yl-4 H -benzo [1,4] oxazin-3-one. 11. A pharmaceutical composition comprising an effective amount of the compound of claim 1 in a Mix with a pharmaceutically acceptable vehicle.

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12. A process to produce a compound substituted benzoxazinone, said process comprises: contact a benzoxazinone from N-arylalkyl of formula

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70

           \ vskip1.000000 \ baselineskip
        

in where:

quad

A_ {1} is a leaving group;

quad

Z, Y, R 1, R 3, R 4, m, n, and p are as are defined in claim 1;

R2 is phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxidiphenyl, diphenyl, methylene diphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxilyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperidinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triacinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, acepinyl, diacepinyl or acridinyl, which is optionally substituted by (R 10) t, where t is from 0 to 4; each R 10 is independently hydrogen, halogen, alkyl, alkoxy, cyano, nitro, amino, urea or ethanesul phylamino; with a heterocyclic compound of the formula:

           \ vskip1.000000 \ baselineskip
        

71

           \ vskip1.000000 \ baselineskip
        

in where:

quad

q is 1 to 3; Y

quad

each of R 5, R 6, R 7, R 8 and R 9 is independently alkyl or hydrogen, or one of R 5 and R 6 together with one of R 7, R 8 and R 9 can form a ring of 5 to 7 members;

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in the presence of a palladium catalyst for produce the benzoxaninone N-arylalkyl compound heterocyclyl-substituted of the formula:

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72

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13. The process of claim 12, said process includes: contact a benzoxaznone from N-arylalkyl of formula

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73

           \ vskip1.000000 \ baselineskip
        

with the heterocyclic compound of formula

           \ vskip1.000000 \ baselineskip
        

74

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such that the benzoxaninone compound of N-arylalkyl heterocyclyl-substituted is formula: 75 and R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, n, p, r and t are as described in claim eleven. 14. The process of claim 11, wherein the leaving groups A 1 are halogen. 15. The use of one or more compounds of any claim 1 to 10 for the preparation of a medicament for the treatment or prevention of a disease of the nervous system central. 16. The use of claim 15, wherein the disease is selected from psychosis, schizophrenia, depressions maniacs, neurological disorders, memory disorders, disorder of attention deficit, Parkinson's disease, sclerosis Amyotrophic lateral, Alzheimer's disease and disease Huntington 17. The use of one or more compounds of any of claims 1 to 9 for the preparation of a medication for the treatment or prevention of a disorder of the gastrointestinal tract.